Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I.
Liu X., Zhang Z., Aguirre T., Shipton ML., Fu L., Du J., Furkert D., Qi J., Chin AC., Riley AM., Liu T., Zhang X., Potter BVL., Fiedler D., Zhu Y., Fu C.
BACKGROUND AND AIMS: Atherosclerotic cardiovascular diseases are the leading cause of death. Apolipoprotein A-I (apoA-I) mediates cholesterol efflux to lower the risks of atherosclerosis. Elevating circulating apoA-I is an effective strategy for atheroprotection. However, the regulatory mechanisms of apoA-I have been elusive. METHODS: Protein-protein interactions were examined by co-immunoprecipitations. Chemical biology tools were used to determine the binding of 5PP-InsP5 to its target proteins and its roles in mediating protein-protein interactions. The mouse atherosclerotic model was generated by injecting AAV-PCSK9 and feeding a Western diet. Atherosclerotic plaques were determined by Oil Red O and H&E staining. RESULTS: We show that blocking IP6K1 activity increases apoA-I production in hepatocytes. IP6K1 binds to apoA-I and via its product 5PP-InsP5 to induce apoA-I degradation, which requires ubiquitination factor E4A (UBE4A). Depleting 5PP-InsP5 by deleting IP6K1 or blocking IP6K1 activity disrupts the interaction between UBE4A and apoA-I, preventing apoA-I degradation, leading to increased production of apoA-I. Hepatocyte-specific deletion of IP6K1 elevates circulating apoA-I levels, which augments cholesterol efflux and lowers the burden of atherosclerosis. Mice with both apoA-I KO and hepatocyte-specific IP6K1 KO were generated to validate that IP6K1 deletion-induced atheroprotection requires apoA-I. CONCLUSIONS: Our findings reveal a mechanism by which blocking IP6K1 boosts apoA-I production. Blocking IP6K1 represents a potential treatment strategy to elevate circulating apoA-I for atheroprotection.